MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia

Overview

Journal Mol Ther Nucleic Acids

Publisher Cell Press

Date 2019 Mar 3

PMID 30825669

Citations 36

Authors

Meijie Qu

Jiaji Pan

Liping Wang

Panting Zhou

Yaying Song

Shuhong Wang

Lu Jiang

Jieli Geng

Zhijun Zhang

Yongting Wang

Yaohui Tang

Guo-Yuan Yang

Affiliations

Soon will be listed here.

Abstract

Studies demonstrate that microRNA-126 plays a critical role in promoting angiogenesis. However, its effects on angiogenesis following ischemic stroke are unclear. Here, we explored the effect of microRNA-126-3p and microRNA-126-5p on angiogenesis and neurogenesis after brain ischemia. We demonstrated that both microRNA (miRNA)-126-3p and microRNA-126-5p increased the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with the scrambled miRNA control (p < 0.05). Transferring microRNA-126 into a mouse middle cerebral artery occlusion model via lentivirus, we found that microRNA-126 overexpression increased the number of CD31/BrdU (5-bromo-2'-deoxyuridine-positive) proliferating endothelial cells and DCX/BrdU neuroblasts in the ischemic mouse brain, improved neurobehavioral outcomes (p < 0.05), and reduced brain atrophy volume (p < 0.05) compared with control mice. Western blot results showed that AKT and ERK signaling pathways were activated in the lentiviral-microRNA-126-treated group (p < 0.05). Both PCR and western blot results demonstrated that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was decreased in the lentiviral-microRNA-126-treated group (p < 0.05). Dual-luciferase gene reporter assay also showed that PTPN9 was the direct target of microRNA-126-3p and microRNA-126-5p in the ischemic brain. We demonstrated that microRNA-126-3p and microRNA-126-5p promoted angiogenesis and neurogenesis in ischemic mouse brain, and further improved neurobehavioral outcomes. Our mechanistic study further showed that microRNA-126 mediated angiogenesis through directly inhibiting its target PTPN9 and activating AKT and ERK signaling pathways.

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References

Li Y, Chopp M, Chen J, Wang L, Gautam S, Xu Y . Intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery after stroke in adult mice. J Cereb Blood Flow Metab. 2000; 20(9):1311-9. DOI: 10.1097/00004647-200009000-00006. View

Gunsilius E, Petzer A, Stockhammer G, Kahler C, Gastl G . Serial measurement of vascular endothelial growth factor and transforming growth factor-beta1 in serum of patients with acute ischemic stroke. Stroke. 2001; 32(1):275-8. DOI: 10.1161/01.str.32.1.275-b. View

Chen J, Zhang Z, Li Y, Wang L, Xu Y, Gautam S . Intravenous administration of human bone marrow stromal cells induces angiogenesis in the ischemic boundary zone after stroke in rats. Circ Res. 2003; 92(6):692-9. DOI: 10.1161/01.RES.0000063425.51108.8D. View

Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L . Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab. 2004; 24(4):441-8. DOI: 10.1097/00004647-200404000-00009. View

Alonso A, Sasin J, Bottini N, Friedberg I, Friedberg I, Osterman A . Protein tyrosine phosphatases in the human genome. Cell. 2004; 117(6):699-711. DOI: 10.1016/j.cell.2004.05.018. View

Kappert K, Peters K, Bohmer F, Ostman A . Tyrosine phosphatases in vessel wall signaling. Cardiovasc Res. 2005; 65(3):587-98. DOI: 10.1016/j.cardiores.2004.08.016. View

Nichols-Larsen D, CLARK P, Zeringue A, Greenspan A, Blanton S . Factors influencing stroke survivors' quality of life during subacute recovery. Stroke. 2005; 36(7):1480-4. DOI: 10.1161/01.STR.0000170706.13595.4f. View

Shen F, Su H, Fan Y, Chen Y, Zhu Y, Liu W . Adeno-associated viral-vector-mediated hypoxia-inducible vascular endothelial growth factor gene expression attenuates ischemic brain injury after focal cerebral ischemia in mice. Stroke. 2006; 37(10):2601-6. DOI: 10.1161/01.STR.0000240407.14765.e8. View

Xiao Z, Kong Y, Yang S, Li M, Wen J, Li L . Upregulation of Flk-1 by bFGF via the ERK pathway is essential for VEGF-mediated promotion of neural stem cell proliferation. Cell Res. 2007; 17(1):73-9. DOI: 10.1038/sj.cr.7310126. View

10.

Chopp M, Zhang Z, Jiang Q . Neurogenesis, angiogenesis, and MRI indices of functional recovery from stroke. Stroke. 2007; 38(2 Suppl):827-31. DOI: 10.1161/01.STR.0000250235.80253.e9. View

11.

Fan Y, Ye J, Shen F, Zhu Y, Yeghiazarians Y, Zhu W . Interleukin-6 stimulates circulating blood-derived endothelial progenitor cell angiogenesis in vitro. J Cereb Blood Flow Metab. 2007; 28(1):90-8. PMC: 2581498. DOI: 10.1038/sj.jcbfm.9600509. View

12.

Fan Y, Yang G . Therapeutic angiogenesis for brain ischemia: a brief review. J Neuroimmune Pharmacol. 2007; 2(3):284-9. DOI: 10.1007/s11481-007-9073-3. View

13.

Zhu W, Fan Y, Frenzel T, Gasmi M, Bartus R, Young W . Insulin growth factor-1 gene transfer enhances neurovascular remodeling and improves long-term stroke outcome in mice. Stroke. 2008; 39(4):1254-61. PMC: 2553752. DOI: 10.1161/STROKEAHA.107.500801. View

14.

Fan Y, Shen F, Chen Y, Hao Q, Liu W, Su H . Overexpression of netrin-1 induces neovascularization in the adult mouse brain. J Cereb Blood Flow Metab. 2008; 28(9):1543-51. PMC: 2581494. DOI: 10.1038/jcbfm.2008.39. View

15.

Fish J, Santoro M, Morton S, Yu S, Yeh R, Wythe J . miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008; 15(2):272-84. PMC: 2604134. DOI: 10.1016/j.devcel.2008.07.008. View

16.

Xiong Y, Mahmood A, Chopp M . Angiogenesis, neurogenesis and brain recovery of function following injury. Curr Opin Investig Drugs. 2010; 11(3):298-308. PMC: 2836170. View

17.

Fan Y, Shen F, Frenzel T, Zhu W, Ye J, Liu J . Endothelial progenitor cell transplantation improves long-term stroke outcome in mice. Ann Neurol. 2010; 67(4):488-97. PMC: 3026588. DOI: 10.1002/ana.21919. View

18.

Le Belle J, Orozco N, Paucar A, Saxe J, Mottahedeh J, Pyle A . Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell. 2011; 8(1):59-71. PMC: 3018289. DOI: 10.1016/j.stem.2010.11.028. View

19.

Sun H, Le T, Chang T, Habib A, Wu S, Shen F . AAV-mediated netrin-1 overexpression increases peri-infarct blood vessel density and improves motor function recovery after experimental stroke. Neurobiol Dis. 2011; 44(1):73-83. PMC: 3179859. DOI: 10.1016/j.nbd.2011.06.006. View

20.

Font M, Arboix A, Krupinski J . Angiogenesis, neurogenesis and neuroplasticity in ischemic stroke. Curr Cardiol Rev. 2011; 6(3):238-44. PMC: 2994116. DOI: 10.2174/157340310791658802. View